1,3-Dihydro-3 -hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, substituted diamino acetate esters and their acid salts in compositions and methods for inducing a calming effect

ABSTRACT

This invention is directed to novel central nervous system depressants of Formula I:   wherein R1 is selected from the group consisting of (lower)alkyl and ar(lower)alkyl; R2 is selected from the group consisting of di(lower)alkylamino(lower)alkyl and diaryl(lower)alkylamino(lower)alkyl; R1 and R2 may be concatenated to form a radical selected from the group consisting of   WHEREIN R4 is selected from the group consisting of (lower)alkyl, aryl, hydroxy(lower)alkyl, ar(lower)alkyl and (lower)alkoxy(lower)alkyl; R5 is selected from the group consisting of (lower)-alkylamino and piperidino; n is an integer from 3 to 5; m is an integer from 1 - 2; r is an integer from 2 to 3; s is an integer from 0 to 6; t is an integer from 0 - 6; with the proviso that the sum of s and t is 3 to 6; R3 is selected from the group consisting of hydrogen, (lower)alkyl, ar(lower)alkyl and (lower)alkoxy(lower)alkyl; X is selected from the group consisting of halogen, cyano, trifluoromethyl, nitro and (lower)alkylthio; Y is selected from the group consisting of hydrogen, halogen, trifluoromethyl, nitro and (lower)alkylthio; and the pharmaceutically acceptable salts thereof, in addition to the method of their preparation and administration and administrable compositions containing the active compounds.

United States Patent [191 McCaully et al.

[451 May 27, 1975 [73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: Oct. 29, 1973 [21] Appl. No.: 410,741

Related US. Application Data [60] Division of Ser. No. 223,712, Feb. 4, 1972, which is a continuation-in-part of Ser. No. 129,638, March 30, I971, abandoned.

[52] US. Cl 424/250; 260/239 D [51] Int. Cl A6lk 27/00 [58] Field of Search 260/2393 D; 424/250 [56] References Cited UNITED STATES PATENTS 1/1967 Bell 260/2393 D 7/1968 Archer et al 260/2393 D OTHER PUBLICATIONS Bell et al., J. Med. Chem., Vol. 11, pp. 457-461, (1968).

Primary Examiner-Stanley J. Friedman Attorney, Agent, or FirmRichard K. Jackson wherein R is selected from the group consisting of (lower)alkyl and ar(lower)alkyl; R is selected from the group consisting of di(lower)alkylamino(1ower)alkyl and diaryl(lower)alkylamino(lower)alkyl; R and R may be concatenated to form a radical selected from the group consisting of wherein R is selected from the group consisting of (lower)alkyl, aryl, hydroxy(lower)alky1, ar(lower)alkyl and (lower)alkoxy(lower)alkyl; R is selected from the group consisting of (1ower)-alkylamino and piperidino; n is an integer from 3 to 5; m is an integer from I 2; r is an integer from 2 to 3; s is an integer from 0 to 6; t is an integer from 0-6; with the proviso that the sum of s and t is 3 to 6; R is selected from the group consisting of hydrogen, (lower)alkyl, ar(lower)- alkyl and (lower)alkoxy(lower)alkyl; X is selected from the group consisting of halogen, cyano, trifluoromethyl, nitro and (lower)alkyltliio; Y is selected from the group consisting of hydrogen, halogen, trifluoromethyl, nitro and (lower)alkylthio; and the pharmaceutically acceptable salts thereof, in addition to the method of their preparation and administration and administrable compositions containing the active compounds.

20 Claims, No Drawings 1,3-DIHYDRO-3- HYDROXY--PHENYL-2H-l,4-BENZODIAZEPIN- 2-ONE, SUBSTITUTED DIAMINO ACETATE ESTERS AND THEIR ACID SALTS IN COMPOSITIONS AND METHODS FOR INDUCING A CALMING EFFECT RELATED APPLICATIONS This application is a division of application Ser. No. 223,712, filed Feb. 4, I972, which is a continuation-inpart of abandoned application Ser. No. 129,638, filed Mar. 30, 1971.

DESCRIPTION OF THE INVENTION This invention relates to the pharmacologically active l,3-dihydro-3-hydroxy-5-phenyI-2H-l ,4 benzodiaZepinQ-one, substituted diamino acetates. The chemical structure of these compounds may be schematically represented by Formula I:

wherein R is selected from the group consisting of (lower)alkyl and ar(lower)alkyl; R is selected from the group consisting of di(lower)alkylamino(lower)alkyl and diar(lower alkylamino(lower)alkyl; R and R may form a radical selected from the group consisting of wherein R is selected from the group consisting of (lower)alkyl, aryl, hydroxy(lower)alkyl, ar(lower)alkyl and (lower)alkoxy(lower)alkyl; R is selected from the group consisting of (lower)alkylamino and piperidino; n is an integer from 3 5; m is an integer from I 2; r is an integer from 2 to 3; s is an integer from 0 6; t is an integer from O 6; with the proviso that the sum of s and I must be 3,4,5 or 6; R is selected from the group consisting of hydrogen, (lower)alkyl, ar(lower- )alkyl and (lower)alkoxy(lower)alkyl; X is selected from the group consisting of halogen, cyano, trifluoromethyl, nitro and (lower)alkylthio; Y is selected from the group consisting of hydrogen. halogen, trifluoromethyl, nitro and (lower)alkylthio; and the pharmaceutically acceptable salts thereof. The hydrated forms of formula I are also within the scope of the invention, the anhydrous and various hydrated forms of each compound being readily prepared by drying the initially formed product.

The term (lower)alkyl is used to include straight and branched chain hydrocarbon groups which contain from one to about six carbon atoms such as methyl, ethyl, i-propyl, n-propyl, n-butyl, n-hexyl and the like. The term (lower)alkoxy is used to include hydrocarbonoxy groups which contain from one to about six carbon atoms such as methoxy, ethoxy, n-propoxy, nbutoxy, n-penoxy and the like. The terms halo and halogen are used to include atoms selected from the group consisting of chlorine, fluorine, bromine and iodine. The terms aryl and arare used to include monovalent, aromatic, hydrocarbon radicals containing six to 10 carbon atoms such as phenyl, tolyl and naphthyl. The term pharmaceutically acceptable acid addition salts is used to include those non-toxic acid addition salts which may be formed with both organic and inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonlic, nitric, p-toluene sulfonic, acetic, citric, maleic, succinic and the like.

The compounds of the invention may be prepared by the following reaction scheme:

III

wherein R, R R, X and Y are the same as hereinabove described and Z is selected from the group consisting of chlorine, bromine and iodine.

The compounds of the invention are prepared by combining a molar quantity of the appropriate 1,3- dihydro-3-hydroxy-5-phenyl-2fi-1,4-benzodiazepin- 2-one halo acetate with 2 to 3 moles of the appropriately substituted diamine in a non-reactive organic solvent that is capable of dissolving the reactants. Suitable examples include xylene, benzene, toluene and tetrahydrofuran. The reaction is preferably carried out at 25 to C. for about 0.5 to about 24 hours. The reaction solvvent is evaporated and the residue is dissolved in a water immiscible organic solvent and is extracted with water.

The organic phase is separated, dried, concentrated and added to a vigorously stirred solution of the appropriate strong pharmaceutically acceptable acid in ether. The compounds of the invention may be filtered and recrystallized from the appropriate solvent.

The compounds of the invention are physiologically active central nervous system depressants.

In the pharmacological evaluation of the biological activity of compounds of this invention, the in vivo effects were tested as follows: The compounds tested were administered orally or intraperitoneally to three mice (14 to 24 grams) at doses ranging from 0.04 to 400 milligrams per kilogram of host body weight (MPK). The animals were watched for a minimum of two hours during which time signs of general stimulation (i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration) and autonomic activity (i.e., miosis, mydriasis, diarrhea) were noted.

Compounds of this invention induce central nervous system depressant effects at dosages of 4.0 MPK per s and lower in the above mentioned host. Thus the compounds of the invention, have demonstrated utility as physiologically active compounds in experimental and comparative pharmacology and are of value in the treatment of mammals, e.g., mice, rats, etc., who are responsive to treatment with central nervous system depressant agents. Specifically the compounds may be administered for the purpose of inducing a calming effect in mammals.

It is particularly important to note that the compounds of the invention are water soluble. This property is of especial significance in preparing dosage formulations wherein a liquid vehicle is required, either for oral or parenteral administration, where the use of a solid drug is not feasible or is contra-indicated as in pre-operative medication where material in the alimentary tract is to be avoided or in the case of a patient unable to swallow a pill or ingest from a solid formulation as in the case of one suffering from delerium tremens.

When the compounds of the invention are employed as described above they may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in tablet or capsule form with conventional flavors, diluents, lubricants, disintegrators or binding agents as may be required. They may be administered orally in the form of a solution or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic. It is most advantageous to provide the compound as a dry powder in a suitable container so that it may be admixed with a suitable aqueous vehicle prior to administration.

A suitable tablet formulation is as follows: 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3- hydroxy 2 11- l ,4-benzodiazepin-2-one, 4-methyl-1-piperazine- A suitable reconstitutable injectable formulation is as follows:

1. 7-chloro-5-( ochlorophenyl l .3-dihydro-3-hydroxy-2fl 1,4-benz0diazepin-2-one. 4-methyl- 1 -piperazineacetate. dihydrochloride dihydrate (packaged with mg. of lactose in a sealed glass am oule) Ve icle: Sterile water for Injection 5 ml containing benzyl alcohol 1% and sodium acetate/acetic acid buffer 0.6%

EXAMPLE 1 7-Ch1oro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy- 21;1-1,4-benzodiazepin-2-one, chloroacetate A mixture of' 7-chloro-5-(o-chlorophenyl)-1,3- dihydro-2fl-1,4-benzodiazepin-2-one, 4-oxide (16 g, 0.05 mole) and chloroacetic anhydride (25 g, 0.145 mole) was heated with stirring at l 10 for 2.5 hours. Ether was then added and the mixture was stirred for 10 minutes. The solid obtained 14.7 g, 75% yield) was filtered, washed with ether and recrystallized from dichloromethane-ether, mp. 232234, nmr (DMSO-D ppm (8); 4.72 (s, 2); 6.10 (s, 1); 7.17 (d, l); 7.48 (m, 6).

Anal. Calcd for C H Cl N o z C, 51.35; H, 2.79; N, 7.05. Found: C, 51.26; H. 2.83; N, 6.94.

Following the procedure of the preceding paragraph react 7-chloro-1,3-dihydro-5-phenyl-2li-l,4- benzodiazepin-2-one, 4-oxide with chloroacetic anhydride to produce 7-chloro-1,3-dihydro-3-hydroxy-5- phenyl-Zfl- 1 ,4-benzodiazepin-2one, chloroacetate.

EXAMPLE 2 7-Ch1oro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy- 1-methyl-2fl-1,4-benzodiazepin-2-one, chloroacetate This compound was prepared by the same procedure as the one described for Example I from 7-chloro-5-(ochlorophenyl)-l ,3-dihydro-1-methyl-2fl-l ,4- benzodiazepin-Z-one, 4-oxide (6.7 g, 0.02 mole) and chloroacetic anhydride (12 g, 0.07 mole). The obtained product (6.8 g, 82.6% yield) had mp. 172l74, nmr (DCCl ppm. (8); 3.51 (s, 3); 4.41 (s, 2); 6.15 (5,

l); 7.19 (d, 1); 7.48 (m, 6).

Anal. Calcd for C H N Cl O C, 52.52; H, 3.18; N, 6.80; Cl, 23.84. F0und1C, 52.27; H, 3.37, N, 6.61; Cl, 25.72.

EXAMPLE 3 7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy- 1 -methyl-2ljl ,4-benzodiazepin-2-one, chloroacetate To a solution of 7-chloro-5-(o-chlorophenyl)-l,3- dihydro-3-hydroxy- 1 -methyl2fl-l ,4-benzodiazepin- 2-one g, 0.03 mole) and 4-dimethylamino-pyridine (3.66 g, 0.03 mole) in 200 ml of tetrahydrofuran, was added chloroacetyl chloride (3.39 g, 0.03 mole). A very heavy precipitate formed instantly. After 10 minutes of stiring, no trace of 7-chloro-5-o-chlorophenyl)- l,3-dihydro-3-hydroxyl -methyl-2H- l ,4- benzodiazepine-Z-one could be detected by thin layer chromatography (silica plates using ether as eluent). The precipitate was filtered off and the filtrate was flash evaporated, to give an oil which crystallized upon addition of ether. Collected 12.1 g (99% yield). The mp, ir and nmr spectra of this product were identical to those described above in Example 2.

Following the procedure of the preceding paragraph, 7-chlorol ,3-dihydro-3-hydroxyl -methyl-5-phenyl- 211-1,4-benZodiazepin-2-one reacts with chloroacetyl chloride to produce the corresponding chloroacetate.

EXAMPLE 4 7-Chloro-5-(o-chlorophenyl)1,3-dihydro-3-hydroxy- 2l -l -l ,4benzodiazepin-2-one, 4-methyl-l-piperazineacetate, dihydrochloride dihydrate A solution of the compound prepared in Example 1 (3 g, 7.5 moles) and N-methylpiperazine (3 ml) in 50 ml of anhydrous tetrahydrofuran was stirred for 16 hours at room temperature. The solvent was flash evaporated and the residue dissolved in dichloromethane was washed repeatedly with saturated aqueous sodium chloride. The organic phase was dried and concentrated to a total volume of 5 ml which was then added to a vigorously stirred solution of gaseous hydrogen chloride in ether. The obtained solid was recrystallized from methanol-ether, collected 1.5 g (33% yield), mp.

202-204 d, nmr (DMSO-D ppm (5), 2.80 (s,3); 3.40 (broad s, 8); 4.23 (s, 2); 5.98 (s, 1); 6.96 (d, l);

Anal. Calcd for C22H22C12N4O32HCL2H2O: c. 46.33; H, 4.95; N, 9.32; H2O, 6.32.

Found: C, 46.11;.

H, 4.34; N, 9.85; H O, 6.40.

The dihydrochloride was soluble in water up to about 30 milligrams per milliliter at room temperature (25C EXAMPLE 5 7-Chloro-5-(o-chlorophenyl )-l ,3-dihydro-3-hydroxyl-methy1-2l;l-l,4-benzodiazepin-2-one, 4-methyl-l-piperazineacetate, dihydrochloride, sesquihydrate This compound was prepared as described in Example 4 from the compound prepared in Example 2 (5 g,

0.012 mole) and N-methylpiperazine. The product obtained (2.5 g, 36% yield) decomposed above 210, nmr (DMSO-D ppm (6), 2.82 (s, 3); 3.43 (broad s, 11); 4.27 (s, 2); 6.00 (s, l); 7.07 (d, l); 7.4-8 (m, 6).

Anal. Calcd for C H Cl N O .2HCl.1 /H O: C, 48.02: H, 5.08; N, 9.74. Found: C, 47.88; H. 4.89; N, 9.78.

The dihydrochloride salt was soluble in water in an amount up to about 30 milligrams per milliliter at room temperature (25C.)

EXAMPLE 6 7-Chloro- 5-(o-chlorophenyl )-l ,3-dihydro-3-hydr0xy- 2l l-1,4-benzodiazepin-2-one, N-(2-dimethylaminoethyl )-N-methylg1ycinate, dihydrochloride, dihydrate Anal. Calcd for C H Cl N O .2HCl.2H O: C, 46.17; H, 5.28; N, 9.79. Found: C, 5.96; H, 5.36; N, 9.85.

EXAMPLE 7 7Chloro-5-(o-chlorophenyl)1-1 ,3-dihydro3-hydroxy- 211- l ,4-benzodiazepin-2-one, 4-( hydroxyethyl)- l -p:iperazineacetate, dihydrochloride, 2%. hydrate The title compound was prepared by the same procedure as that described in Example 4 from the compound prepared in Example 1 and N-(2-hydroxyethyl)- piperazine. The product was obtained in 46% yield from ethanol-ether, it became dark above and decomposed above 202, nmr (DMSO-D ppm(5), 3.1-4.2 (braod m, 16), 4.55 (broad s, 2), 6.03 (s, 1), 7.01 (d, l), 7.3-7.8 (m, 6).

H, 5.13; N, 9.29; H O, 7.39.

Found: C, 45.34;

H, 4.70; N, 9.33; H O, 7.39.

EXAMPLE 8 By a procedure analogous to that described in Example 4 the following compounds in which R and R are concatenated may be prepared.

4-methyl-1-piperazineacetate, hydrochloride, hydrate An aqueous solution of 7-chloro-5-(o-chlorophenyl)- 1 ,3-dihydro-3-hydroxy-2fl-1,4-benzodiazepin-2-one, 4-methyl-l-piperazineacetate, dihydrochloride, dihydrate (29 g., 0.05 mole) prepared as described in Example 4, was neutralized with an excess of 1N sodium hydroxide and was extracted with dichloromethane. The organic phase was dried and evaporated to give a fine white powder, 18.5 g. (80% yield), nmr (DCC1 ppm (8), 2.27 (s, 3), 2.55 (broad s,4), 2.70 (broad s, 4), 3.57 (s, 2), 6.08 (s, 1), 7.08 (d, l), 7.2-7.9 (m, 6).

A solution of equimolar quantities of 7-chloro-5-(ochlorophenyl)-1,3-dihydro-3-hydroxy-2fl-1,4- benzodiazepin-2-one, 4-methyl-piperazineacetate, dihydrochloride, dihydrate and the above obtained free base (2.3 millimoles of each) in methanol was stirred at room temperature for 30 min. The solvent was flash evaporated and the residual foam was recrystallized from methanol ether, to give 2 g. (82% yield) of white solid, mp. 233-234 C, nmr (DMSO-D ppm (5), 2.81 (s, 3), 3.05 (broad m, 4), 3.35 (broad m, 4), 3.67 (s,2), 5.95 (s, 1), 7.00 (d, 1), 7.3-7.8 (m, 6).

Anal. Calcd. for C H Cl N O .HCl.H O: C, 51.22;

H, 4.89; N, 10.86; Cl, 20.62.

Found: C, 51,44;

H, 4.56; N, 10.74; Cl, 20.91.

By repeating the foregoing technique for producing a monohydrochloride salt, employing 7-chloro-1,3- dihydro-3-hydroxy-5phenyl-2l;l-1,4-benzodiazepin- 2-one, chloroacetate or 7-chlor0-1,3-dihydro-3-hydro- 3-hydroxyl -methyl-5-pheny1-2l;l- 1 ,4-benzodiazepin- 2-one, chloroacetate as the initial reactant, the corresponding S-phenyl and l-methyl-S-phenyl analogues of the title compound are prepared.

EXAMPLE 1 l 7-Ch1oro-5-(o-chlorophenyl l .3-dihydro-3-hydroxy- 21 1-1,4-benzodiazepin-2-one, 4-methyl- 1 -piperazinacetate, methane sulfonate, hydrate (broad m, 4), 3.4 (broad m, 4), 3.65 (s, 2), 5.95 (s, 1),

Anal. Calcd. for C H Cl N,O;,.CH,SO;,.H O: C. 48.00; H, 4.90; N, 9.74; Cl. 12.32

Found: C. 48.08;

H, 4.71; N, 9.41; C], 12.62.

The methane sulfonate salt was soluble in water in amounts greater than 300 milligrams per milliliter at room temperature (25C.)

By repeating the foregoing technique for producing a methane sulfonate salt employing 7-chloro-1,3- dihydro-3-hydroxy-5-phe,nyl- 2l ;l-1,4-benzodiazepin- 2-one, chloroacetate or 7-chloro-1,3-dihydro-3- 5 hydroxy-1-methy1-5-phenyl-2lj-1,4-benzodiazepin- 2-one, chloroactate as the initial reactant, the correspondingg 5-phenyl and l-methyl-5-phenyl analogues of the title compound are prepared.

EXAMPLE 12 7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy- 2H- 1 ,4-benzodiazepin-2-one, 4-methyl-l-piperazineacetate, maleate, hemihydrate To a methanolic solution of 7-chloro-5-(och1orophenyl)-1,3-dihydro-3-hydroxy-2lj-1,4- benzodiazepin-2-one, 4-methy1- 1 -piperazineacetate (2.3 g., 5 mmoles) prepared as described in Example 10, was added maleic acid (0.58 g., 5 mmole). The so 20 lution was stirred at room temperature for 30 min. The solvent was then flash evaporated and the residue was recrystallized from methanol-ether to give 1.5 g. (51% yield) of white crystalline product which did not melt sharply but slowly decomposed above 125, nmr (DMSO-D ppm (8), 2.92 (s, 3), 3.0 (broad s, 4), 3.4 (broad s, 4), 3.63 (s, 2), 6.02 (s, 1), 6.30 (s, 2), 7.1 (d, 1), 7.3-7.9 (m, 6).

Anal. Calcd. for C H Cl N O .C,H,O AH O: C, 53.25; H, 4.64; N, 9.55; CI. 12.09.

Found: C, 52.96. H, 4.53, N, 9.46; C1, 1196.

EXAMPLE 13 7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxyl-methyl-ZH- 1 ,4-benzodiazepin-2-one, 4-methyl- 1 -piperazineacetate, hydrochloride, hydrate An aqueous solution of 7-chloro-5-(o-chlorophenyl)- l,3-dihydro-3-hydroxy- 1 -methyl-2l l-1 4- benzodiazepin-2-one, 4-methyl-1 -piperazineacetate, dihydrochloride, sesquihydrate (11.6 g, 0.02 mole) prepared as described in Example 5, was neutralized with an excess of 1N sodium hydroxide and was extracted with dichloromethane. The organic phase was dried and evaporated to give a fine powder 9.1 g. (94.6% yield); nmr (DCCI ppm (8), 2.27 (s, 3), 2.57 (broad m, 4), 2.65 (broad m, 4), 3.46 (s, 3), 3.55 (s, 2), 6.10 (s, 1), 7.10 (d, 1), 7.2-7.9 (m, 6).

A solution of equimolar quantities of 7-ch1oro-5-(ochlorophenyl)-l,3-dihydro-3-hydroxy-1-methyl-2lj- 1,4-benzodiazepin-2-one, 4-methyl-l-piperazineacetate, dihydrochloride, sesquihydrate, and the above obtained free base (20 millimoles of each) in methanol was stirred at room temperature for 30 min. The solvent was flash evaporated and the residual foam was rcrystallized from methanol ether, to give 15 g. (71% yield) of solid, mp. 270-271C; nmr (DMSO-D ppm (8) 2.87 (s, 3), 3.1 (broad m, 4), 3.4 (broad m, 4), 3.49 (s, 3), 3.70 (s, 2), 6.07 (s, 1), 7.12 (d, 1), 7.5-7.9 (m, 6).

Anal. calcd for C ,,H ,Cl N O,-,.HCLH O: C, 51.13: H, 5.14; Found: C, 52.34: H. 4.75;

N, 10.57LC1. 20.08.

EXAMPLE 14 7-Chloro-5-(o-chlorophenyl)-l,3-dihydro-3-hydroxyl-methyl-Zlj-l ,4-benzodiaZepin-2-one, 4-methyl-l-piperazineacetate, methanesulfonate To a solution of 7-chloro-5-(o-chlorophenyl) l,3- 5 hydroxy-l -methyl-2fll ,4benzodiazepin-2-one, 4-methyl-l-piperazineacetate 197.5 g, 0.4 moles) pre pared as described in Example 13, was added methane sulfonic acid (38.8 g., 0.4 moles). The solution was stirred at room temperature for 30 minutes. The solvent was then flash evaporated and the residue was recrystallized from methanol ether to give 196 g. (85.5% yield) of white crystalline product, mp. 23824l, nmr (DMSO-Dg) Ppm (5), 2.48 (s, 3), 2.87 (s, 3), 3 broad m, 4), 3.3 (broad m, 4), 3.48 (s, 3), 3.68 (s, 2), 6.02 (s, 1), 7.10 (m, l) 7.57.95 (m, 6).

Anal. Calcd for C H Cl N O .CH SO C, 50.44; H, 4.94; N, 9.80; C], 12.41; s, 5.61. Found: C, 50.32; H, 4.94; N, 9.771Cl, 12.4l; S. 5.67.

The methane sulfonate salt was soluble in water at room temperature (25C) in amounts up to and ex- 25 ceeding 300 milligrams per milliliter.

What we claim is:

1. A process for inducing a calming effect in a warmblooded animal which comprises administering to said animal an effective amount of a compound of the formula:

LRO

l; OCOCH N N-R in which R is a member selected from the group consisting of hydrogen, (lower)alkyl, ar(lower)alkyl' and (lower)alkoxy(lower)alkyl;

R is a member selected from the group consisting of (lower)alkyl and hydroxy(lower)alkyl;

X is a member selected from the group consisting of halogen, cyano, trifluoromethyl, nitro and (lower )alkylthio;

Y is a member selected from the group consisting of hydrogen, halogen, trifluoromethyl, nitro and (lower)alkylthio;

now a pharmaceutically acceptable salt thereof.

2. The process of claim 1 in which said compound is a hydrochloride salt of 7-chloro-5-(o-chlorophenyl) l,3 dihydro-3-hydroxy-2H-1,4-ben2odiazepin-2'one, 4-methyll -piperazineacetate.

3. The process of claim 1 in which said compound is a hydrochloride salt of 7-chloro-5-(ochlorophenyl) 1,3-dihydro-3-hydroxyl -methyl-2H l ,4- bcnzodiazepin-Z-one, 4-methyl-l-piperazineacetate.

4. The process of claim 1 in which said active ingredient is a methane sulfonate salt of 7-chloro-5(ochlorophenyl )1 .3-dihydro-3-hydroxy-2H- l ,4- benzodiazepin-Z-one, 4methyll -piperazineacetate.

5 141 5. The process oficlaim 1 in which said compound is a methane sulfonate salt of 7-chloro-5-(ochlorophenyl)-l ,3-dihydro-3-hydroxy-l -methyl-2l-l- 1,4-benzodiazepin-2-one, 4"-methyl- 1 -piperazineacetate.

6. The process of claim 1 in which said compound is a hydrochloride salt of 7-chloro-l,3-dihydro-3- hydroxy-5-phenyl-2H- l ,4 benzodiazepin-2-one, 4methyl- 1 -piperazineacetate. r

7. The process of claim 1 in which said compound is a methane sulfonate salt of 7chloro-l ,3-dihydro-3- hydroxy-S-phenyLZH- l ,4-benzodiazepin-2-one, 4 methyl- 1 -piperazineacetate.

8. The process of claim 1 in which said compound is a hydrochloride salt of 7-chloro-1,3-dihydro-3- hydroxyl -methyl-5-phenyl-2ll-l-l ,4-benzodiazepin- 2-one, 4-methyl-l-piperazineacetate.

9. The process of claim 1 in which said compound is a methane sulfonate salt of 7-chloro-l ,3-dihydro-3- hydroxyl -methyl-5-phenyl-2l-ll ,4-benzodiazepin 2-one, 4-methyl-l-piperazineacetate.

10. The process of claim 1 in which said compound is a hydrochloride salt of 7-chloro-5 (o-chlorophenyl) l,3-dihydro-3-hydroxy-2H- l ,4-benzodiazepin-2-one, 4-(hydroxyethyl)-1-piperazineacetate.

11. A composition of matter useful for inducing a calming effect in mammals comprising, as the essential active ingredient, a compound of the formula:

(lower)alkoxy(lower)alkyl;

R is a member selected from the group consisting of (lower)alkyl and hydroxy(lower)alkyl;

X is a member selected from the group consisting of halogen, cyano, trifluoromethyl, nitro and (lower- )alkylthio;

Y is a member selected from the group consisting of hydrogen, halogen, trifluoromethyl, nitro and (lower)alkylthio;

now a pharmaceutically acceptable salt thereof; and a pharmaceutical adjuvant, in unit dosage form containing from 0.5 to 35 milligrams of said active ingredient.

12. The composition of claim 11 in which said active ingredient is a hydrochloride salt of 7-chloro-5-(ochlorophenyl)-l ,3-dihydro-3-hydroxy-2H- l ,4- benzodiazepin-2-one, 4-methyl-l-piperazineacetate.

13. The composition of claim 11 in which said active ingredient is a hydrochloride salt of 7-chloro-5-(ochlorophenyl l ,3-dihydro-3-hydroxyl -methyl-2H- 1,4-benzodiazepin-2-one, 4--methyl- 1 -piperazineacetate.

14. The composition of claim 111 in which said active ingredient is a methane sulfonate'salt of 7-chloro-5-(ochlorophenyl )-l ,3-dihydro-3-hydroxy-2H- l ,4- benzodiazepin-2-one, 4-methyl-l -piperazineacetate.

18. The composition of claim 11 in which said active ingredient is a hydrochloride salt of 7-ch1oro-l,3- dihydro-3-hydroxy-l-methyl-S-phenyl-ZH-1,4- benzodiazepin-Z-one, 4-methyl-1 -piperazineacetate.

19. The composition of claim 11 in whhich said active ingredient is a methane sulfonate salt of 7-chloro- 1,3-dihydro-3-hydroxyl -methyl-5-phenyl-2H-l ,4- benZodiazepin-2-one, 4-methyl- 1 -piperazineacetate.

20. The composition of claim 11 in which said active ingredient is a hydrochloride salt of 7-chloro-5-(ochlorophenyl)-l,3-dihydro-3-hydroxy-2H-1,4- benzodiazepin-2-one, 4-(hydroxyethyl)-1-piperazineacetate.

b UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,886,276 DATED May 27, 1975 INVENTOR(S) Ronald J. McCaully, Abraham Nudelman, Stanley C. Bell It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 13, line 57, delete "now" and insert or Column 14, line 35, the moiety of the structural formula containing the piperazine ring should appear as follows D l 4 -OCOCH N N- R Column 14, line 53, delete "now" and insert or Signed and Scaled this isr:.u. Eighteenth D of April 1978 Arrow:

RU'HI (I \IASON LI'TRELLE F. PARKER -"mg ()j/rcer Acting Commissioner of Patents and Trademarks 

1. A PROCESS FOR INDUCING A CALMINING EFFECT IN A WARMBLOODED ANIMAL WHICH COMPRISES ADMINISTERING TO SAID ANIMAL AN EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMUL:
 2. The process of claim 1 in which said compound is a hydrochloride salt of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2 -one, 4-methyl-1-piperazineacetate.
 3. The process of claim 1 in which said compound is a hydrochloride salt of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-1-methyl-2H-1,4 -benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 4. The process of claim 1 in which said active ingredient is a methane sulfonate salt of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2 -one, 4-methyl-1-piperazineacetate.
 5. The process of claim 1 in which said compound is a methane sulfonate salt of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-1-methyl-2H-1,4 -benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 6. The process of claim 1 in which said compound is a hydrochloride salt of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 7. The process of claim 1 in which said compound is a methane sulfonate salt of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, 4 methyl-1-piperazineacetate.
 8. The process of claim 1 in which said compound is a hydrochloride salt of 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 9. The process of claim 1 in which said compound is a methane sulfonate salt of 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 10. The process of claim 1 in which said compound is a hydrochloride salt of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one, 4-(hydroxyethyl)-1-piperazineacetate.
 11. A composition of matter useful for inducing a calming effect in mammals comprising, as the essential active ingredient, a compound of the formula:
 12. The composition of claim 11 in which said active ingredient is a hydrochloride salt of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2 -one, 4-methyl-1-piperazineacetate.
 13. The composition of claim 11 in which said active ingredient is a hydrochloride salt of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-1-methyl-2H-1,4 -benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 14. The composition of claim 11 in which said active ingredient is a methane sulfonate salt of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2 -one, 4-methyl-1-piperazineacetate.
 15. The composition of claim 11 in which said active ingredient is a methane sulfonate salt of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-1-methyl-2H-1,4 -benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 16. The composition of claim 11 in which said active ingredient is a hydrochloride salt of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 17. The composition of claim 11 in which said active ingredient is a methane sulfonate salt of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 18. The composition of claim 11 in which said active ingredient is a hydrochloride salt of 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 19. The composition of claim 11 in whhich said active ingredient is a methane sulfonate salt of 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 4-methyl-1-piperazineacetate.
 20. The composition of claim 11 in which said active ingredient is a hydrochloride salt of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2 -one, 4-(hydroxyethyl)-1-piperazineacetate. 